Our filgotinib program in RA

Our filgotinib program in RA

RA is a chronic autoimmune disease that affects ~3 million patients in the U.S. and the five largest European markets. RA is characterized by inflammation and degeneration of the joints. Patients suffer from pain, stiffness, and restricted mobility due to a persistent inflammation of multiple joints, ultimately resulting in irreversible damage of the joint cartilage and bone. According to GlobalData, sales of RA therapeutics across the 10 main healthcare markets was $21.7 billion in 2017, with the current market being dominated by injectable, biological therapies. Biologics, mostly TNF therapies, need to be injected and often lose their effect over time, so there continues to be a considerable unmet need with regard to efficacy, safety, and convenience of use with existing treatments.

New oral therapies that target the Janus kinase, or JAK, signaling pathway are emerging to treat inflammatory diseases; non-specific JAK inhibitors, however, have a range of side effects, including aberrations in low-density lipoprotein, or LDL, cholesterol and red blood and NK cell counts. We discovered JAK1 in an inflammation target discovery assay in 2003 and subsequently discovered filgotinib as a JAK1 specific inhibitor small molecule. In a human whole blood assay we demonstrated that filgotinib, with a nearly 30-fold selectivity for JAK1 over JAK2 and for JAK1 over JAK3, is more selective for JAK1 than any other JAK inhibitor known to us to be either approved for sale or in clinical development in inflammation; these findings were independently corroborated by Dr. Iain McInnes (“Ex Vivo Comparison of Baricitinib, Upadacitinib, Filgotinib, and Tofacitinib for Cytokine Signaling in Human Leukocyte Subpopulations,” ACR 2017).

The high selectivity of filgotinib for JAK1 may allow for a positive efficacy profile, with an improved safety profile for filgotinib due to the improved selectivity over JAK2 and JAK3.

Filgotinib
Highly JAK1 selective

Highly JAK1 selective (bar chart)

Our clinical program for filgotinib for RA

Clinical trials to date have shown that filgotinib is well-tolerated, with atherogenic index improvement, absence of anemia, low infection rates and low incidence of deep venous thrombosis and pulmonary embolisms. We believe its once-a-day oral dosage and its low risk for drug-drug interactions make it convenient for patient use.

We reported final 24‑week data from DARWIN 1 (594 patients, add-on to methotrexate) and DARWIN 2 (283 patients, monotherapy) Phase 2b dose-range finding clinical trials in insufficient methotrexate responders with moderate to severe RA in 2015. Both trials achieved the primary endpoints (ACR20). Below are the ACR50 and ACR70 scores at 12 and 24 weeks for 100 and 200 mg qd in both DARWIN 1 and DARWIN 2:

ACR 50/70 scores – DARWIN 1 and DARWIN 2 (bar chart)

Overall, there was no statistically relevant difference between the once-daily and twice-daily dosing regimens in DARWIN 1. Both trials showed a rapid onset of activity, as of week one for ACR and DAS28(CRP) responses. In DARWIN 1 (200 mg bid) and in DARWIN 2 (100 mg qd) up to 50% of the patients reached low disease activity or remission. The 100 mg and 200 mg qd doses achieved similar levels of activity overall.

Below follows information regarding activity of filgotinib, other JAKs, and another mechanism (anti-TNF) of RA treatment in separate patient trials; JAKs have scored higher on ACR50% in recent trials than the mechanism most often used today:

Superior activity JAK class in RA

Superior activity JAK class in RA (ACR50%) (bar chart)

Note: data from separate studies not conducted by the Company

Filgotinib’s improvement in hemoglobin shown in DARWIN 1 and 2 potentially differentiates it when compared to impact on hemoglobin shown by other JAK inhibitors in their respective RA trials:

Hemoglobin

Filgotinib’s improvement in hemoglobin (bar chart)

Note: data from separate RA studies not conducted by the Company. filgotinib – Westhovens et al., and Kavanaugh et al., ARD 2016; baricitinib – Dougados et al., Annrheumdis 2016, RA-BUILD; tofacitinibFDA AdComm briefing document May 2012; upadacitinib – Genovese et al. ACR 2017

Rheumatoid arthritis patients experience a decrease in natural killer (NK) cells as a consequence of their disease. Filgotinib’s lack of impact on NK cells shown in DARWIN 1 and 2 potentially differentiates it when compared to the impact on NK cells shown by other JAK inhibitors in their respective RA trials:

NK cells

Filgotinib’s impact on NK cells (bar chart)

Note: data from separate RA studies not conducted by the Company. filgotinib – Westhovens et al., and Kavanaugh et al., ARD 2016; baricitinib – Dougados et al., Annrheumdis 2016, RA-BUILD and Tanaka EULAR 2016 abstract RA-BEAM; tofacitinib – Van Vollenhoven abstract 2013, median CFB at W6; upadacitinib – Genovese et al. A&R 2016 BALANCE 2.

Rheumatoid arthritis patients experience platelet elevation as a consequence of their disease. Filgotinib’s reduction of platelets to more normal levels, as shown in DARWIN 1 and 2, potentially differentiates it when compared to the impact on platelets shown by other JAK inhibitors in their respective RA trials:

Reduction of platelets

Filgotinib’s reduction of platelets (bar chart)

Note: data from separate RA trials and not conducted by the company. filgotinib – DARWIN 1 W12 results; baricitinib – Dougados et al., Annrheumdis 2016; tofacitinib – FDA AdComm briefing document May 2012, *upadacitinib – for data see graph below, Genovese et al. ACR 2017

Mean Platelet Levels (line chart)

Source: Genovese et al. ACR 2017

Also due to its high selectivity for JAK1, filgotinib has shown the lowest rates of infection, deep venous thrombosis (DVT), and pulmonary embolisms (PEs) per 100 patient year experience (PYE) versus other JAKs and other therapy types thus far in their respective trials in RA:

Low incidence DVT and infections

Event
Per 100 PYE

filgotinib

upadacitinib

baricitinib

tofacitinib

tocilizumab

adalimumab

(50-)200mg daily
DARWIN 3 Wk 84

6 and 12mg BID

2 and 4mg QD

5mg bid

4 and 8 mg / kg

 

 

Genovese, ACR2017

Genovese et al., ACR2017

Genovese et al., ACR2017

Wollenhaupt et al., ACR2017

Genovese et al., ACR2012

Burmester et al., 2011

Note: data from separate RA studies not conducted by the Company.

(1)

DVT / PE data on tofacitinib from Mease et al, ACR 2017, 5mg bid

Patient year exposure

1,708

725

6,637

5,891

14,994

23,943

Serious infection

1.5

2.3

2.9

2.2

4.5

4.6

Herpes Zoster

1.2

3.7

3.2

3.6

NR

NR

DVT / PEs

2 / 1,708

5 / 725

31 / 6,754

3 / 1,849(1)

N cases / 100PY

0.1

0.7

0.5

0.2

DARWIN 3 is a multi-center, open-label, long-term follow-up safety and efficacy trial of subjects who have completed either DARWIN 1 or DARWIN 2. All subjects started the trial at the same dose level, either at 200 mg once per day or at 100 mg twice per day (except for males in the U.S. sites of these trials who receive a maximum daily dose of 100 mg), depending on the regimen administered during the preceding trial, with DARWIN 1 subjects continuing to use filgotinib in combination with MTX.

Galapagos and Gilead reported findings from DARWIN 3 at 60 and 84 weeks of treatment in the course of 2017. Promising activity levels were maintained and favorable findings relating to tolerability profile were reported; data from both time points in DARWIN 3 were consistent with the risk/benefit profiles reported in DARWIN 1 and 2, as presented by Dr. Mark Genovese at ACR 2017 (“Long-term Safety of Filgotinib in the Treatment of Rheumatoid Arthritis: Week 84 Data from a Phase 2b Open-Label Extension Study”).

FINCH Phase 3 program with filgotinib in RA

In August 2016, Gilead initiated the FINCH global Phase 3 program investigating the efficacy and safety of 100 mg and 200 mg filgotinib once daily, in RA patient populations, ranging from early stage to biologic-experienced patients:

FINCH 1 is a 52‑week, randomized, placebo- and adalimumab-controlled trial in combination with methotrexate (MTX) in an expected 1,650 patients who have had inadequate response to MTX. The primary endpoint is ACR20 at week 12. ACR20 response rate signifies a 20% or greater improvement in the number of swollen and tender joints as well as a 20% or greater improvement in three out of five other disease-activity measures. ACR50 and ACR70 reflect the same, respectively for 50% and 70% response rates. The trial will also include radiographic assessment at weeks 24 and 52. We expect Gilead to complete recruitment for FINCH 1 in Q2 2018.

FINCH 2 is a 24‑week, randomized, placebo-controlled trial in an expected 423 patients who are on conventional disease-modifying anti-rheumatic drugs (cDMARD), and have had an inadequate response to biological treatment. The primary endpoint is ACR20 at week 12. We and Gilead expect to report topline findings from the FINCH 2 trial in H2 2018.

FINCH 3 is a 52‑week, randomized trial in an expected 1,200 MTX-naïve patients to study filgotinib in combination with MTX, as well as monotherapy. The primary endpoint is ACR20 at week 24. Radiographic progression will also be assessed. We expect Gilead to complete recruitment for FINCH 3 in Q3 2018.

Gilead is performing a single dedicated male patient safety trial in UC patients concurrent to all Phase 3 programs.